Progesterone Inhibits Cholesterol Biosynthesis in Cultured Cells
ACCUMULATION OF CHOLESTEROL PRECURSORS (*)
- From the Department of Human Genetics and The Eccles Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah 84112
- §Established Investigator of the American Heart Association. To whom correspondence should be addressed.
Abstract
Cells acquire cholesterol through endogenous synthesis and through receptor-mediated uptake of cholesterol-rich low density lipoprotein (LDL). Esterification of LDL-derived cholesterol is catalyzed by acyl-CoA:cholesterol acyltransferase (ACAT) in the endoplasmic reticulum (ER). Progesterone inhibits esterification, and, although the mechanism of inhibition is not completely understood, this inhibition results from progesterone's ability to inhibit the activity of multiple drug resistance (MDR) P-glycoproteins (P. DeBry and J. E. Metherall, submitted for publication). In the current manuscript, we demonstrate that progesterone inhibits cholesterol biosynthesis resulting in the accumulation of a number of sterol precursors. In Chinese hamster ovary (CHO) cells, high concentrations (100 μM) of progesterone completely blocked cholesterol production, resulting in the accumulation of lanosterol and a lanosterol precursor. Lower concentrations (40 μM) of progesterone cause plasma membrane accumulation of several sterol products. The majority of these sterols are precursors of cholesterol since they were efficiently converted to cholesterol upon removal of progesterone from the culture medium. Although very high concentrations (>200 μM) of progesterone killed CHO cells, their growth was restored by the addition of cholesterol to the growth medium, indicating that progesterone toxicity resulted from cholesterol auxotrophy. The effect of progesterone was not unique to CHO cells; progesterone also inhibited cholesterol biosynthesis in all human cell lines tested. These observations suggest that a common progesterone-sensitive pathway is involved in both cholesterol biosynthesis and the processing of LDL-derived cholesterol.
Footnotes
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↵* This work was supported in part by grants from the American Heart Association and the Primary Children's Research Foundation of Utah. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are:
- ER
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endoplasmic reticulum
- ACAT
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acyl-CoA:cholesterol acyltransferase
- LDL
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low density lipoprotein
- CHO
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Chinese hamster ovary
- LPPS
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newborn calf lipoprotein-deficient serum
- FCS
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fetal calf serum
- 7-DHC
-
7-dehydrocholesterol
- BSA
-
bovine serum albumin.
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↵2P. DeBry and J. E. Metherall, submitted for publication.
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- Received August 23, 1995.
- Revision received October 23, 1995.
- © 1996 by The American Society for Biochemistry and Molecular Biology, Inc.
